Abnormal signal transduction pathways are well-recognized targets for anticancer chemotherapy. For the purpose of cancer intervention, two signal transduction pathways have drawn enormous attention as potential targets for anticancer chemotherapy.
The Receptor Tyrosine Kinase (RTK)→Ras→Raf-1→MEK→ERK signal transduction pathway has been intensively studied. It was one of the earliest and best elucidated pathways, and its deregulation is frequently associated with human cancers. The first level targets are RTKs. For example, erbB2/HER-2 receptor is commonly over-expressed in human breast cancer and ovarian cancers. As important is epidermal growth factor receptor (EGFR) deregulation. Agents targeted to EGFR, HER-2, platelet-derived growth-factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR) and also RTK-associated kinases such as Src are currently under pre-clinical development, in clinical trials and on the market.
Downstream of RTK is Ras, which has been found to mutate frequently in human cancers. Activating point mutations of small GTPase Ras are present in about 30% of all human tumors. Constitutively active Ras induces growth factor independent cell proliferation and cell survival. The oncogene nature of Ras was shown by malignant transformation of epithelial cells by mutant Ras (i.e., Harvey Ras). Several agents have been tested clinically to block Ras. Ras antisense oligonucleotides block Ras translation, while farnesyl transferase inhibitors (FTIs) prevent Ras from proper post-translation modification (i.e., prenylation) and activation.
Further downstream in the RTK→Ras→Raf-1→MEK→ERK signal transduction pathway is Raf-1. Efforts for blocking Raf-1 led to discovery of a small-molecule Raf-1 kinase inhibitor BAY 43-9006, which is now in a phase I clinical trial in patients with advanced solid tumors. Raf-1 Antisense ISIS 5132 has entered phase II clinical trials in patients with advanced colon and lung cancers. A MEK inhibitor CI-1040 has shown promising preclinical pharmacologic results and has entered a phase I clinical trial for safety evaluation. Mitogen-activated protein kinases (MAPKs) are over-expressed in certain cancers such as human head and neck squamous cell carcinomas. This led to targeting MAPKs, such as ERK, c-Jun N-terminal kinase (JNK) and p38 for anticancer therapy. One example is ERK inhibitor PD98059, which has shown synergism with docetaxel in inducing apoptosis of androgen-independent human prostate cancer cells. JNK inhibitor SP600125 and JNK antisense molecules reduce proliferation of all breast cancer cell lines. Moreover, inhibitors of p38 (i.e., PD169316, SB203580 and SB202190) can augment bisphosphonate (BPs)-induced growth inhibition of breast carcinoma.
The p53 tumor suppressor gene plays an indispensible role in two key processes: to induce cell cycle arrest at the G1/S transition along with DNA repair, or if DNA repair is impossible, to activate apoptosis. The p53 protein functions through transcriptional activation of various downstream effecter genes (i.e., CDK inhibitor p21CIP1/WAF), which have promoters containing p53-specific binding sites. Mutation of p53 is observed in over half of all sporadic cancers, making p53 mutations the most common genetic change in human cancers. The first strategy in targeting p53 is via MDM2, an oncogene that antagonizes p53 function by either repressing transcription of p53 or by induction of ubiquitin-mediated proteolysis of p53. Peptide inhibitors and antisense oligonucleotides against MDM2 showed positive results in model cancer cells. Another strategy is to reactivate p53 in tumor cells. This includes gene delivery using adenovirus (ONYX-015), which can only replicate in mutant p53 cells. Small molecules that stabilize p53 (i.e., CP-31398) have also received clinical interest.
Apoptosis of cancer cells is induced by many chemotherapeutic agents. Progress in elucidation of apoptosis machinery and mechanism has provided numerous potential molecular targets for anticancer therapy. One important family of apoptosis proteins is the BCL2 family. BCL2, an oncoprotein, has become an important target for anticancer chemotherapy since BCL2 deregulation has been frequently associated with malignant transformation and acquisition of drug resistance. One approach to turn off BLC2 is by antisense oligonucleotides such as G3139, which is now under phase II/III clinical trials.
Some endogenous angiogenisis inhibitors (e.g., angiostatin and endostatin) have been used clinically against tumor angiogenisis and metastasis. Angiostatin is a proteolytic fragment of collagen type XVIII. Clinical studies showed positive results when they were used either alone or in combination with other chemotherapeutic agents.
Accordingly, a need exists for new chemotherapeutic agents which can induce apoptosis in cancer cells. New agents should be have toxicity that is highly selective towards cancer cells at nM levels as well as have potent antitumor activities.